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Lipid nanoparticles as oral vehicles of immunotherapy

a technology of lipid nanoparticles and immunotherapy, which is applied in the direction of drug compositions, peptide/protein ingredients, metabolic disorders, etc., can solve the problems of t1d autoreactivity development that is much longer, remains quite elusive, and is not easy to be detected and treated, and achieves the potential for local and systemic pathophysiologic effects, low bioavailability, and low bioavailability

Pending Publication Date: 2022-10-27
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about a new way to treat type 1 diabetes (T1D) using lipid nanoparticles. These particles can penetrate the intestinal barrier and accumulate in specific parts of the body, like the pancreas and lymph nodes. There, they can deliver an anti-inflammatory agent and a specific autoantigen (insulin b-peptide) to promote tolerance and reduce the risk of T1D. The treatment is short, minimizes side effects, and may help improve the effectiveness of existing treatments. The patent also describes the use of a small molecule inhibitor (Tofacitinib) that can prevent the activation of certain immune cells and promote transplant survival in a model of transplantation. It suggests that this approach could be a transformative treatment for T1D patients, avoiding chronic immunosuppression and associated side effects.

Problems solved by technology

Differently from transplantation, where the timing of exposure to antigens is well defined, the development of autoreactivity in diseases like T1D spans a much longer period and remains quite elusive.
Unfortunately, administration of native insulin by this route leads to rapid enzymatic degradation in the stomach and intestinal lumen, resulting in low bioavailability.50 Oral administration of insulin is also hampered by its low permeability with respect to the intestinal mucosa.51 The use of permeation enhancers is one strategy to improve bioavailability, but brings the risk of carrying toxins and pathogens to the systemic bloodstream with the potential for local and systemic pathophysiologic effects49.

Method used

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  • Lipid nanoparticles as oral vehicles of immunotherapy
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  • Lipid nanoparticles as oral vehicles of immunotherapy

Examples

Experimental program
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Effect test

example 1

[0111]Targeted Jak inhibition synergizes with CoB to prolong transplant survival.

[0112]The feasibility of combining CTLA4-Ig with a short-course Tofa administration in a full MHC mismatch (C57BL / 6 to BALB / c) mouse heart transplantation model was tested (FIG. 1A). Encouragingly, heart transplant survival in mice treated with CTLA-4Ig was significantly improved by a short course (10 days) of Tofa (MST untreated: 9d, CTLA4-Ig only: 36d, Tofa+CTLA4-Ig: 120d). This improvement was evident even in mice receiving hearts kept ischemic for 4 h before transplantation—a more clinically relevant scenario—where CTLA4-Ig efficacy is undermined by early accumulation of inflammatory mediators67 (MST untreated: 9d, CTLA4-Ig only: 26.5d, Tofa+CTLA4-Ig: 150d). Analysis of the graft infiltrate by flow cytometry revealed that the protective effect of the combination of Tofa+CTLA4-Ig was associated the accumulation of a much higher frequency of Treg cells (FIG. 1B). Moreover, ex-vivo restimulation of spl...

example 2

[0113]Targeted Jak inhibition limits DC maturation.

[0114]To better understand the impressive protective effect achieved with the combination Tofa+CTLA4-Ig, we tested the ability of Tofa to inhibit the maturation of bone marrow derived dendritic cells (DC) in response to LPS (FIG. 2). Exposure to Tofa caused a significant inhibition of the up-regulation of CD80 and CD86 costimulatory molecules, with a concomitant reduction in release of the prototypical inflammatory cytokines IL-6 (not shown), IL-1, and TNF-α. The latter two have been implicated in T1D development and inhibition of their accumulation would be a valuable effect. Interestingly, Tofa did not prevent the up-regulation of MHC-II molecules, rendering DC with high Signal 1 but very low Signal 2 (costimulatory molecules) and low Signal 3 (cytokines)—a phenotype that could maximize the impact of CTLA4-Ig on reactive T cells.

example 3

[0115]Tofa does not interfere with Treg suppression of T cells.

[0116]The observed accumulation of Treg in transplants treated with Tofa+CTLA4-Ig warranted confirmation that Tofa (although transient) would not interfere with Treg function. The results of a T cell CFSE-Proliferation-Assay conducted to assess the suppressive activity of Treg (added at either 2:1 or 4:1 T cell to Treg ratio) without and with Tofa (at 0.5 or 1 μM) confirmed the preservation of regulatory activity (FIG. 3). These results show the potential of the combined use of Tofa with CTLA4-Ig for induction of long-term regulation.

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Abstract

Lipid nanoparticle compositions for use in immunomodulation and treatment of autoimmune and related diseases such as Type 1 Diabetes are provided along with methods for using same.

Description

REFERENCE TO RELATED APPLICATIONS[0001]This application is a § 371 U.S. National Entry Application of PCT / US2020 / 026574, filed Apr. 3, 2020, which claims the benefit of U.S. Provisional Patent Application No. 62 / 828,743, filed on Apr. 3, 2019 and U.S. Provisional Patent Application No. 62 / 858,775, filed on Jun. 7, 2019, each of which are hereby incorporated by reference for all purposes as if fully set forth herein.STATEMENT OF GOVERNMENTAL INTEREST[0002]This invention was made with government support under grant HL127355 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Autoimmune diseases are pathologies caused by the erroneous attack of a patient immune system against an organ or tissues of the own body. Autoimmune diseases are often treated with immunosuppressants that weaken the entire immune system, leaving patients vulnerable to infection. An ideal autoimmune therapy establishes immune tolerance t...

Claims

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Application Information

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IPC IPC(8): A61K9/51A61K31/519A61K31/541A61K38/28
CPCA61K9/5123A61K31/519A61K31/541A61K38/28A61P3/10B82Y5/00A61K9/1075A61K9/0053
Inventor RAIMONDI, GIORGIOPATRONE, JULIACALDERON-COLON, XIOMARATIBURZI, OLIVIA
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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